Ivabradine and pharmaceutically acceptable salts thereof, particularly hydrochloride thereof, have highly valuable pharmacological and therapeutic effects, especially bradycardiac effects, so that these compounds can be used not only in the treatment or prevention of various clinical symptoms of myocardial ischemia such as angina, myocardial infarction and associated rhythm disorders, but also for the treatment or prevention of various rhythm disorders, especially supraventricular rhythm disorder. Ivabradine is an effective drug of treatment of myocardial ischemia such as angina pectoris and the like.
U.S. Pat. No. 5,296,482 (the '482 patent) describes a synthetic route of Ivabradine in detail. Furthermore, the '482 patent describes a method of resolving compounds of formula (II) to obtain a compound of formula (I), using camphor sulfonic acid. However, the result of that resolving method is far from satisfactory. First, that resolving method has a very low yield. The yield of the compound of formula (I) by using camphor sulfonic acid as a resolving agent is only 4-5%, which results in the total yield of only 2-3%. Such a low yield leads to high cost and low efficiency. Second, because of the low selectivity of the resolving agent, the enantiomer excess (ee) value of the resolved product is low. Several re-crystallization steps are needed to complete the resolution of the compound. Furthermore, the process is complicated and not suitable for industrial production. The chiral purity of the final product is not satisfactory either.
In view of the medicinal value of Ivabradine and salts thereof, it is necessary to find an effective industrial method to obtain the S configuration of the intermediate compound of formula (I) with high chiral purity, in high efficiency and high yield.